Molecular mechanisms in hippocampal impairment induced by endocrine disrupters

本研究旨在探讨三甲基锡（TMT）对海马功能损害的分子机制。TMT是某些塑料的副产品，与众所周知的内分泌干扰物三丁基锡和三苯基锡密切相关。发现TMT在给药后4-5天开始诱导CA 3锥体细胞的严重损失以及CA 1细胞的中度损失。这种神经元死亡之前，血浆皮质酮，这是部分阻断白细胞介素-1受体拮抗剂的预处理的早期和短暂的升高。在行为上，TMT中毒的特点是早期和短暂的癫痫发作，随后是持续的攻击和学习障碍。因此，TMT诱导下丘脑-垂体-肾上腺轴的早期激活，推测之前的免疫活性细胞因子的参与，这可能会触发神经元死亡通过糖皮质激素（GC）受体在hippocamp.Further研究设计与肾上腺切除术和管理的组合使用的I型和II型特异性GC受体激动剂。通过甲吡酮给药抑制血浆皮质酮的早期升高导致CA 1细胞死亡的挽救，但不导致CA 3细胞的挽救，并且随后导致学习障碍的至少部分改善。地塞米松，一种II型GC受体激动剂，但不是醛固酮，一种I型受体激动剂，阻断TMT大鼠的神经元和行为障碍。还检测了细胞因子如IL-1α和IL-1 β的参与。皮质酮或地塞米松的补充治疗取消了肾上腺切除术诱导的IL-1α和IL-1β表达的增强，表明TMT诱导的OL-1α和OL-1β的产生通过II型GC受体调节。

The present study was conducted in order to study the molecular mechanisms of the impairment in hippocampal functions following the administration of trimethyltin (TMT). TMT is a byproduct of certain plastics, and closely related to well known endocrine disruptors, tributyltin and triphenyltin. TMT was found to induce a profound loss of CA3 pyramidal cells as well as a moderate loss of CA1 cells, starting 4-5 days after dosing. This neuronal death was preceded by an early and transient elevation of plasma corticosterone, which was partially blocked by the pretreatment of interleukin-1 receptor antagonist. Behaviorally, TMT intoxication was characterized by an early and transient development of seizures, followed by a persistent aggression and learning impairments. It is thus suggested that TMT induced an early activation of hypothalamo-pituitary-adrenal axis, presumably preceded by the involvement of immuno-active cytokines, which may trigger the neuronal death via glucocorticoid (GC) receptors in the hippocampus.Further study was designed with use of a combination of adrenalectomy and administration of type I and II specific GC-receptor agonists. The suppression of an early elevation of plasma corticosterone by means of metyrapone adinistration resulted in the rescue of CA1 cell death, but not of CA3 cells, and subsequently, at least a partial improvement of learning impairments., Dexamethasone, a type II GC receptor agonist, but not aldosterone, a type I receptor agonist, blocks both the neuronal and behavioral impairment in TMT rats. The involvement of cytokines such as IL-1α and -1β were also examined. Supplemental treatment with corticosterone or dexamethasone cancelled adrenalectomy-induced enhancement of IL-1α and-1β expression, suggesting that TMT-induced OL-1α and-1β production was regulated via type II GC receptors.